Single cell approaches define neural stem cell niches and identify microglial ligands that can enhance precursor-mediated oligodendrogenesis

Ashleigh Willis; Danielle Jeong; Yunlong Liu; Marissa A Lithopoulos; Scott A Yuzwa; Paul W Frankland; David R Kaplan; Freda D Miller

doi:10.1016/j.celrep.2024.115194

Single cell approaches define neural stem cell niches and identify microglial ligands that can enhance precursor-mediated oligodendrogenesis

Cell Rep. 2025 Jan 15;44(1):115194. doi: 10.1016/j.celrep.2024.115194. Online ahead of print.

Authors

Ashleigh Willis¹, Danielle Jeong², Yunlong Liu³, Marissa A Lithopoulos⁴, Scott A Yuzwa³, Paul W Frankland⁵, David R Kaplan⁶, Freda D Miller⁷

Affiliations

¹ Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
² Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
³ Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
⁴ Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
⁵ Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Psychology, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁶ Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁷ Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: [email protected].

PMID: 39823226
DOI: 10.1016/j.celrep.2024.115194

Abstract

Here, we used single cell RNA sequencing and single cell spatial transcriptomics to characterize the forebrain neural stem cell (NSC) niche under homeostatic and injury conditions. We defined the dorsal and lateral ventricular-subventricular zones (V-SVZs) as two distinct neighborhoods and showed that, after white matter injury, NSCs are activated to make oligodendrocytes dorsally for remyelination. This activation is coincident with an increase in transcriptionally distinct microglia in the dorsal V-SVZ niche. We modeled ligand-receptor interactions within this changing niche and identified two remyelination-associated microglial ligands, insulin growth factor 1 and oncostatin M, that promote precursor proliferation and oligodendrogenesis in culture. Infusion of either ligand into the lateral ventricles also enhanced oligodendrogenesis, even in the lateral V-SVZ, where NSCs normally make neuroblasts. These data support a model where gliogenesis versus neurogenesis is determined by the local NSC neighborhood and where injury-induced niche alterations promote NSC activation, local oligodendrogenesis, and likely contribute to myelin repair.

Keywords: CP: Neuroscience; CP: Stem cell research; insulin-like growth factor 1; microglia; myelin; neural stem cells; oligodendrogenesis; oncostatin M; remyelination; scRNA-seq; single cell spatial transcriptomics; white matter injury.